AMG900

Reagent Authentication Certificate:

Chemical Probes Portal AMG900.pdf

Protein target name:

AURKA, AURKB, AURKC

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

Up to 100 nM

Probe Availability

MedChem Express (945595-80-2)

Cayman (945595-80-2)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

cell cycle-regulated kinase

HUGO ID:

HGNC:11393 HGNC:11390 HGNC:11391

Entrez gene ID:

6790 9212 6795

UNIPROT ID:

O14965 Q96GD4 Q9UQB9

Target alias:

AIK, ARK1, AURA, BTAK, PPP1R47, STK15, STK6, STK7; AIK2, AIM-1, AIM1, ARK2, AurB, IPL1, PPP1R48, STK12, STK5; AIE2, AIK3, ARK3, AurC, HEL-S-90, SPGF5, STK13

Probe Details

Chemical Probes Portal ID:

CPP110

Probe alias:

AMG 900, AMG-900

PubChem CID:

24856041

ChEMBL ID:

CHEMBL2140408

SMILES string:

CC1=CSC(=C1)C2=NN=C(C3=CC=CC=C32)NC4=CC=C(C=C4)OC5=C(C=CC=N5)C6=NC(=NC=C6)N

InChi Key:

IVUGFMLRJOCGAS-UHFFFAOYSA-N

Orthogonal probe:

MK-5108XMD-12AZD1152

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

<5 nM

Potency assay:

enzyme inhibition assay: AURKA IC50 = 5 nM; AURKB IC50 = 4 nM; AURKC IC50 = 1 nM

Off target activity

Off target protein and potency:

p38 alpha IC50 = 53 nMTYK2 IC50 = 220 nMJNK2 IC50 = 520 nMMET IC50 = 550 nMTIE2 IC50 = 650 nM

Potency assay (off target):

AMG900 was tested in enzyme inhibition assays and ATP-competitive binding assays (Ambit Biosciences). IC50s are from enzyme inhibition assays. In ATP-competitive binding assays, AMG900 had KD < 50 nM for the Aurora kinases, DDR1, DDR2, and LTKR.

In cell validation

On target activity in cells

Potency in cells:

IC50

6.5-8.2 nM

Potency assay (cells):

In HeLa cells, IC50s were measured in substrate phosphorylation assays using quantitative cell imaging. The IC50 varied slightly by substrate.

Target engagement assay (cells):

Indirect, substrate phosphorylation assays

In vivo validation

Organism:

mouse

Dose:

3.75-15 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

xenograftbone marrow

Target engagement assay:

Indirect: in xenografts and bone marrow, AMG900 inhibited phosphorylation of substrates for Aurora kinases.

Primary Reference

Reference (doi):

10.1158/0008-5472.CAN-10-3001

Reference (PMID):

20935223

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

AMG900 is a potent pan Aurora inhibitor that is active in tumor cell lines irrespective of P-gp or BCRP status. Compound is orally bioavailable in mice, rats, dogs and monkeys.

Jun 11 2016 - 4:24am

AMG900 is an orally available, small molecule, ATP-competitive, low single-digit nM, pan-Aurora-kinase inhibitor (AKI). It shows at least 10-fold in vitro selectivity compared with relevant Janus kinase family members, and among other targets including MET, p38, and TIE2. It has shown activity in more than three dozen cell lines, shows time-dependent activity, and is effective in cell lines resistant to antimitotics such as paclitaxel and to other AKIs, alone or with microtubule-targeting agents. Combination therapy with HDAC inhibitors and low doses of AMG900 shows promise. Histone H3 phosphorylation is a useful biomarker.

Jun 11 2016 - 4:25am

AMG900 is a potent ATP-competitive inhibitor of Aurora kinases. It exhibits low nanomolar affinity for Aurora kinases (A, B, and C); it also has low nanomolar affinity for DDR1, 10-100 nanomolar affinity for DDR2, LTK, FES, and TIE, and 100-200 nanomolar affinity for 5 additional kinases. It is cell permeable (with low nanomolar potency) and orally bioavailable. AMG900 inhibits Aurora kinase autophosphorylation in cells and the phosphorylation of the Aurora kinase substrate histone H3 in a dose-dependent manner. It inhibits the proliferation of 26 tumor cell lines, including cell lines that are resistant to paclitaxel and other Aurora kinase inhibitors. For the purpose of interrogating Aurora kinase function specifically, it might be important to test alongside other Aurora kinases inhibitors with different off-target profiles.

Dec 27 2016 - 2:30pm

AMG900

Probe Availability

Probe Information

Target Details

AIK, ARK1, AURA, BTAK, PPP1R47, STK15, STK6, STK7; AIK2, AIM-1, AIM1, ARK2, AurB, IPL1, PPP1R48, STK12, STK5; AIE2, AIK3, ARK3, AurC, HEL-S-90, SPGF5, STK13

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AMG900

Probe Availability

Probe Information

Target Details

AIK, ARK1, AURA, BTAK, PPP1R47, STK15, STK6, STK7; AIK2, AIM-1, AIM1, ARK2, AurB, IPL1, PPP1R48, STK12, STK5; AIE2, AIK3, ARK3, AurC, HEL-S-90, SPGF5, STK13

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?